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Apoprotein A-V: An important regulator of triglyceride metabolism

Summary Apolipoprotein A-V (apoA-V) was discovered in 2001 both by comparative sequencing and as a liver regeneration protein. The gene is a located at the APOA1/C3/A4/A5 gene cluster on chromosome 11q23, a locus well known for playing a major role in regulating plasma cholesterol and triglyceride (TG) levels. ApoA-V is produced in the liver and has very low plasma concentrations (0.1–0.4 μg/ml). Mice lacking apoA-V have 4-fold increased TG levels, whereas apoA-V overexpression leads to 40% plasma TG reduction. Based on metabolic studies in vivo, apoA-V enhances the catabolism of TG rich lipoproteins rather than affecting their intestinal or hepatic production. By activating proteoglycans-bound lipoprotein lipase (LPL), apoA-V can accelerate TG hydrolysis from VLDL and chylomicrons independent from other apoproteins. Several variants at the APOA5 gene locus have been detected in humans. Some single nucleotide polymorphisms (SNPs) are associated with significantly higher plasma TG levels in patients (e.g., −1131T > C, S19W, G185C). In addition, these SNPs may affect fibrate response and obesity. However, data for a possible association of APOA5 variants with coronary heart disease are not consistent. Severe structural mutations (Q139X, Q148X, IVS3 + 3G > C) predispose to familial hypertriglyceridaemia and late-onset chylomicronaemia. Thus, despite its low plasma concentration, apoA-V is a major regulator of plasma TG metabolism in humans. However, the precise mechanism of its function is not yet clear. Competing interests: None declared Presented at the Annual Symposium of the SSIEM, Hamburg, 4–7 September 2007.     

The Effects of a Health Care–Based Brief Intervention on Dating Abuse Perpetration: Results of a Randomized Controlled Trial

Prevention Science - Dating abuse (DA) is prevalent and consequential, yet there are no evidence-based interventions for the health care setting that prevent perpetration. The current study’s...     

Brain injury severity and autonomic dysregulation accurately predict heterotopic ossification in patients with traumatic brain injury

OBJECTIVE: To assess brain injury severity, autonomic dysregulation and systemic infection as risk factors for the occurrence of heterotopic ossification in patients with severe traumatic brain injury. DESIGN: Historic cohort study. SETTING: Radboud University Medical Centre. SUBJECTS: All consecutively admitted patients with severe traumatic brain injury (admission Glasgow Coma Scale score 8 or less) during the years 2002-2003. MAIN MEASURES: The development of clinically relevant heterotopic ossification, defined as painful swelling of joints with redness and decreased range of motion, confirmed radiographically. RESULTS: Seventy-six (64%) of the 119 patients survived and were eligible for further follow-up. Nine patients (12%) developed 20 symptomatic heterotopic ossifications, in one or more joints. Patients with heterotopic ossification had sustained more severe brain injuries, compared to the group without heterotopic ossification. The mean coma duration in the heterotopic ossification group was 28.11 days (SD 20.20) versus 7.54 days (SD 7.47) in the patients without heterotopic ossification (P < 0.001). The occurrence of autonomic dysregulation (relative risk (RR) 59.55, 95% confidence interval (CI) 8.39-422.36), diffuse axonal injury (RR 20.68, 95% CI 4.92-86.91), spasticity (RR 16.96, 95% CI 3.96-72.57) and systemic infection (RR 13.12, 95% CI 3.01-57.17) were all associated with an increased risk of developing symptomatic heterotopic ossification. However, only autonomic dysregulation had a high positive (88.9%, 95% CI 51.7-99.7) and negative (98.5%, 95% CI 91.9-99.9) predictive value with regard to heterotopic ossification. CONCLUSIONS: The occurrence of autonomic dysregulation may predict the chance of developing heterotopic ossification in patients with severe head injury.     

Transitions to and from at-risk alcohol use in adults in the United States

Introduction: The objective of this research is to study transitions to and from at-risk alcohol use.

Methods: Logistic regression analyses (done 2015–2016) assessed transitions to and from past-year at-risk drinking in a representative sample of U.S. adults surveyed twice (in 2001–2002 and 2004–2005).

Results: Among 34,653 adults, 28% reported at-risk use at time 1. Of those, 73% had at-risk use at time 2. Of those without at-risk use at time 1, 15% reported at-risk use at time 2. Positive high-risk drinking transition predictors were, at time 1, being young, male, white, childless, in good to excellent health, ever smoking, using drugs, military membership (time 1 but not 2), and becoming divorced or separated by time 2. Positive low-risk drinking transition predictors were being elderly (age ≥ 65), female, non-white, never smoking or using drugs, no alcohol use disorder, alcohol treatment, and, after time 1, having children.

Conclusions: Many adults transition to and from at-risk alcohol use; youth is the strongest positive predictor of transition to at-risk and not transitioning to low-risk drinking. Persons transitioning to legal drinking age are most likely to transition to high-risk and least likely to low-risk drinking.     

Contextualizing single‐arm trials with real‐world data: An emulated target trial comparing therapies for neovascular age‐related macular degeneration

AbstractOne‐in‐four ophthalmology trials are single‐armed, which poses challenges to their interpretation. We demonstrate how real‐world cohorts used as external/synthetic control arms can contextualize such trials. We herein emulated a target trial on the intention‐to‐treat efficacy of off‐label bevacizumab (q6w) pro re nata relative to fixed‐interval aflibercept (q8w) for improving week 54 visual acuity of eyes affected by neovascular age‐related macular degeneration. The bevacizumab arm (n = 65) was taken from the ABC randomized controlled trial. A total of 4,471 aflibercept‐treated eyes aligning with the ABC trial eligibility were identified from electronic health records and synthetic control arms were created by emulating randomization conditional on age, sex, and baseline visual read via exact matching and propensity score methods. We undertook an inferiority analysis on mean difference at 54 weeks; outcomes regression on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to −15 Early Treatment Diabetic Retinopathy (ETDRS) letters at week 54; and a time‐to‐event analysis on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to −15 ETDRS letters by week 54. The findings suggest off‐label bevacizumab to be neither inferior nor superior to licensed aflibercept. Our study highlights how real‐world cohorts representing the counterfactual intervention could aid the interpretation of single‐armed trials when analyzed in accord to the target trial framework. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

One‐in‐four randomized controlled trials in ophthalmology are single‐armed, which poses challenges for interpreting their efficacy relative to standard of care. Recent conceptual advances in the methods of causal inference and in the emulation of target trials suggests that the standard‐of‐care arms representing the counterfactual intervention can be approximated with observational data.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How real‐world cohorts representing the counterfactual intervention can aid the interpretation of single‐armed ophthalmological trials.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study highlights how real‐world cohorts representing the counterfactual intervention could aid the interpretation of single‐armed ophthalmological trials when undertaken in accord with the target trial framework.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

External counterfactual arms could reduce the time and cost to reach potential regulatory approval.     

Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis

Background

Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor—ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF.

Methods

A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by acoustic radiation force impulse imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy.

Results

A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients <20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p < 0.0001). Glycine-conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97).

Conclusions

ARFI SWV and bile acid profiles provide evidence for early increase in liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.     

Diagnostics in inflammatory bowel disease: ultrasound

Diagnosis of chronic inflammatory bowel diseases （IBD） is based on a combination of clinical symptoms, laboratory tests and imaging data. Imaging of the morphological characteristics of IBD includes the assessment of mucosal alterations, transmural involvement and extraintestinal manifestations. No single imaging technique serves as a diagnostic gold standard to encompass all disease manifestations. Ultrasound, computed tomography （CT） or magnetic resonance imaging （MRI） allow cross-sectional imaging of the transmural alterations and extraintestinal manifestations. While in the USA the technique of choice is CT, in Europe the focus is more on MRI and ultrasound （US）. Most patients with chronic IBD are diagnosed at a young age. After baseline diagnosis many of these young patients have to undergo repetitive imaging procedures during the variable clinical course of the disease, characterized by alternate periods of remission and active disease, and in monitoring the response to treatment. US has the advantage of being noninvasive, less costly, and easily repeatable, and thus can be very useful in following up patients with IBD. In addition, rising concern about radiation exposure in young adults indicates the demand for radiation-sparing techniques like US and MRI. This article focuses on the current clinical practice of US in IBD, describing the current technologies used in transabdominal intestinal US and the characteristic sonographic findings in Crohn′s disease and ulcerative colitis.     

Hepatic transit time of an echo enhancer: an indicator of metastatic spread to the liver

OBJECTIVE: Can sonographic measurements of the transit time of an echo enhancer from the hepatic artery to the hepatic vein discriminate between patients with and without liver metastases? METHOD: The hepatic transit time (hepatic artery to hepatic vein delay) of an echo enhancer (Optison) was measured in pulse inversion mode on the basis of time intensity curves (TIC) in patients with gastrointestinal tumours with proven liver metastases and in patients without liver metastases. RESULTS: Sixty-four patients (46 males, 18 females, mean age 61 +/- 13 years) were admitted to the study. Fourteen patients had metastatic growth in the liver with a primary tumour in situ (group A). Fourteen patients had liver metastases following primary tumour resection (group B). Twenty-eight patients had a known primary tumour but no liver metastases (group C), and eight patients had neither liver symptoms nor a primary tumour (group D). The mean hepatic transit time in patients with liver metastases was 6.6 +/- 1.8 s in group A and 6.7 +/- 1.7 s in group B, whereas in patients without liver metastases it was significantly longer; namely, 15.7 +/- 4.4 s in group C and 15.0 +/- 2.0 s in group D (P < 0.001). The transit times in all patients with liver metastases were < or = 10 s, while in all patients without metastases except for four the times were > or = 12 s and one of the four had already developed liver metastases on early follow-up. CONCLUSIONS: Measurement of the hepatic transit time permits discrimination of patients with and without liver metastases.